Small Nerve Fiber Neuropathy Commonly Found in Fibromyalgia (and Linked to Central Sensitization)

Sometimes you don’t know if you should laugh or cry. This study starts off with a list of abnormal findings in fibromyalgia: there’s the central nervous system sensitization which involves increased activity in the brain’s pain processing regions, increased responsiveness in regions that that process ‘noxious stimuli’, and there’s an inability to become habituated to painful stimuli (the pain should diminish over time – not get worse!).

But then, the authors say, we really don’t have any idea what’s causing fibromyalgia! In fact, researchers know several of the things that have gone wrong in fibromyalgia, but they don’t know what’s causing them to go wrong. This study could bring us closer to what’s causing things to go wrong.

A recent study suggested that pain processing centers of the brain in young people protect themselves from a kind of pain signal ‘assault’ by ‘bulking up’ (increasing grey matter) and decoupling themselves from each other. Both of these attempts get reversed in older patients leaving one more hypersensitive to pain.

This pain signal assault could be generated in three places in the body that I know of, and probably more: at the dorsal horn of the spinal cord (which filters signals to the brain), at the sensory ganglia, or in the sensory nerves. The study examined the sensory nerve network emanating from the skin to see if it was damaged and was sending unusual signals to the brain.

The Study

Researchers commonly stimulate the nervous system to see how it responds. In this study, laser-evoked potential (LEP) tests specifically targeted the small nerve fibers that carry the messages from the skin to the spinal cord. As the laser heated up the skin, the researchers examined the electrical charge in the small nerve fibers to determine if they were functioning properly.

Because the small nerve fibers carry pain signals, they could be involved in producing the neuropathic (nerve) pain present in fibromyalgia and chronic fatigue syndrome. Until recently, however, studies assessing small nerve fiber neuropathy in fibromyalgia and chronic pain disorders have been rare. Now some small studies suggest rates of small fiber neuropathy (SFN) in FM could be quite high.

This was a big study. Laser evoked potentials were done three times each in three different places in 199 patients as well as 109 age- and sex-matched controls. Skin biopsies to assess small fiber density were taken in three places each in 20 patients and 60 controls.

As a laser evoked pinprick and burning sensations at three tender points, the researchers measured the laser-evoked potentials produced and asked the participants to assess the amount of pain they experienced. The corresponding amplitude and habituation of the electrical response was measured.

The Findings

Nervous System Activity

The laser pinpricks evoked, not increased, but reduced electrical responses ( e.g. amplitude) from the sensory nerves in most FM patients relative to the controls. The reduced strength of the electrical signals resulting from stimulation by the laser indicated problems with the nerves were present.

People with migraine and FM tended, on the other hand, to have normal or increased response. This suggested that a very different subset was embedded in the larger fibromyalgia population.

Habituation

“The tendency not to habituate across consecutive sessions of painful stimulation seems to be a stable pattern in fibromyalgia, which is not infuenced by psychological factors and is correlated to illness severity” – Authors

The nervous system should quickly become habituated to and respond less vigorously to the laser pricks over time; indeed, the strength of the electrical signal (the evoked potential) dropped by almost 50% by the third pinprick in the healthy controls, but by only about 15% in the FM patients.

This suggested that FM patients’ nervous systems were inordinately provoked by the initial pain signals and had trouble turning them off. This kind of continuing arousal can be seen in a number of instances in FM and ME/CFS: in contracting muscles that never completely relax in FM, in a heart rate that does not calm down during rest, and in a sympathetic nervous system activation that doesn’t stop in both disorders.

One might also include the flu that never ends for many chronic fatigue syndrome patients. In both disorders an event (infection, trauma) triggers a response (sickness behavior and/or pain) that should get ameliorated over time, but the return response, which should swing the system back to homeostasis, doesn’t kick in.

In this case the anti-nociceptive or anti-pain pathways descending from the brain were not kicking in to ameliorate the pain present in fibromyalgia.

Migraine and Fibromyalgia Subset

That was bad enough, but a subset of patients with FM and migraine (40% of the group) probably had the worst of it. By the third pinprick their nervous system response had not only not habituated, but had significantly increased indicating that their pain response system was revving up when it should have been revving down.

Migraine is becoming an ever more interesting aspect of both FM and ME/CFS. Rates of migraine appear to be quite high in both disorders, and it will no doubt be taken more into account in future studies. The authors suggested that the increased central sensitization in migraine this study showed was present could cause fibromyalgia to occur without any increase in pain signals from the body at all; i.e., the migraines are setting the foundation for FM to more easily occur.

This inability to reduce the central nervous system response to pain signals turned out to be important, as it was associated more than any other finding with reduced quality of life and increased pain levels at the FM tender points.

Small Fiber Neuropathy Found

“Our present opinion, which needs further confrmation by the enlargement of the skin biopsy data, is that idiopathic peripheral sensory nerve involvement may be part of FM syndrome.” – Authors

Small nerve fiber neuropathy (reduced nerve fiber density) was present in 90% of the 21 patients tested. The authors noted that it was different from the kind of SFN usually seen. This finding buttressed the finding of a recent study that also found reduced electrical signal responses in FM patients and which postulated that SFN was present.

Recent studies suggest a strong genetic component is present in both fibromyalgia and chronic fatigue syndrome, and SFN may be heritable as well. A gene mutation causing hyperexcitability in the dorsal root ganglion neurons that process the pain signals is associated with severe neuropathic pain. (A mutation that reduces dorsal ganglia excitability is associated with indifference to pain.)

This study found considerable evidence of small fiber neuropathy, but the findings suggested that the lack of habituation by the central nervous system played more of a role in producing pain than the nerve fiber problems leading from the skin to the spinal cord. (That finding, however, was based on a small sample size.)

The authors suggested, however, that the small nerve fiber problems they found in the skin probably extended to the nerve fibers associated with the muscles and joints, and that ion channel dysregulation probably caused both the small fiber problems and the neuron problems associated with central sensitization. (A sodium channel polymorphism has been associated with severe fibromyalgia.)

In short, they believe the same general problem is causing the small nerve fiber problems in the skin, muscles. and joints, as well as neuron problems in the brain and spinal cord.

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About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising.

Unfortunately much of the thinking about pain modulation, habituation and control is focused on endogenous modulation eg. stressful environments and cognition mediation of perception, such as in the following review:

Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions

Roland Staud

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373184/

This process is well established and useful and actions such as meditation (mindfullness) do help to reduce pain.

However there is much to do on understanding the immunological and chemotactic effects on neuropeptides and as a consequence on pain generation within the nervous system (neuropathy or neuralgia).

It has been known for years that the immune system mediates pain via low grade inflammatory process and that glial cells are a centre of neuro-immune pain influence:

http://www.ncbi.nlm.nih.gov/pubmed/15755561

In auto-immune arthritis Nerve-growth factor (NGF) and its pathways mediates the pain which is reduced by blocking NGF:

http://www.ncbi.nlm.nih.gov/pubmed/15927377

The connection between neuropathies and immune function are well quite studied with clear causation:

Antibodies to neuronal antigens and some neurokinins have been reported and cytokines, sensitize nociceptive signalling in the peripheral and central nervous systems.

The role of the immune system in the generation of neuropathic pain.
Calvo M, Dawes JM, Bennett DL. Lancet Neurology 2012 Jul;11:629-642

I have worked in the area of post-operative neuropathy, originally as a psychologist because it was long thought that this phenomenon was cognitive but I switched my opinion (because that is all it was ) to a better understanding of the immunology involved. Now I know that post operative neuropathy is immunological. Psychological factors can heighten the distress and the pain but they are not the originator of the unusual pain. To give an example: a patient has surgery on the knee but afterwards complains of a lot of pain in their shoulder and constant nausea believing they were handled badly in theatre. After scans of the shoulder showed very slight inflammation probably from a very old sporting injury but the pain radiated well away from the sight. The symptoms persisted so more investigated was warranted. Mapping the pain suggested a neuropathy and spinal fluid showed elevated neurokinins, in particular Substance P. After giving an antagonist (aprepitant) the nausea declined and so did the neuropathy.

It is very important to balance investigations into fibromyalgia from all perspectives. The fact that around 40%+ people with ME have FM and ME is probably primarily an immunological disorder.

To me most of the evidence says that FM is a neuro-immune disorder this means one of two things. The nervous system is "irritated" by infection, injury or stress which initiates immune involvement. The corollary of this is that the immune system becomes dysfunctional and "attacks" (auto-immune) the nervous system, ie antibodies are created to specific neuropeptides the consequence of which is cellular transport dysfunction eg. channelopathy. Of course all of these are possibilites because each one is supported by the evidence.

I was reading your response to fibro being possibly connected to a immune problem. I am being treated with Cymbalta to ease the pain; which is does. Do you think using a anti depressant is basically just disguising the symptoms and doing nothing about the underlying problem, which you think is immunity related? Do you have fibro, and if so, what do you take to help your pain I tend to agree that it has much to do with "stress", as I have been under many years of stress...and then fibro symptoms occurred. Thanks.